西亚试剂：：Ligand-Induced Architecture of the Leptin

发布时间：2025-09-15

Liliya V. Mancour1, 2, Hikmat N. Daghestani1, Somnath Dutta1, Gerwin H. Westfield1, 2, Justin Schilling1, Austin N. Oleskie1, Jeffrey F. Herbstman1, Steven Z. Chou1, Georgios Skiniotis1, 2

 

Despite the crucial impact of leptin signaling on metabolism and body weight, little is known about the structure of the liganded leptin receptor (LEP-R) complex. Here, we applied single-particle electron microscopy (EM) to characterize the architecture of the extracellular region of LEP-R alone and in complex with leptin. We show that unliganded LEP-R displays significant flexibility in a hinge region within the cytokine homology region 2 (CHR2) that is connected to rigid membrane-proximal FnIII domains. Leptin binds to CHR2 in order to restrict the flexible hinge and the disposition of the FnIII “legs.” Through a separate interaction, leptin engages the Ig-like domain of a second liganded LEP-R, resulting in the formation of a quaternary signaling complex. We propose that the membrane proximal domain rigidification in the context of a liganded cytokine receptor dimer is a key mechanism for the transactivation of Janus kinases (Jaks) bound at the intracellular receptor region.

丙烯醛肉桂醛桂皮醛4-硝基肉桂醛

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